Acute effects of ventilator hyperinflation with increased inspiratory time on respiratory mechanics: randomized crossover clinical trial.
To evaluate the effects of ventilator hyperinflation on respiratory mechanics. A randomized crossover clinical trial was conducted with 38 mechanically ventilated patients with pulmonary infection. The order of the hyperinflation and control (without changes in the parameters) conditions was randomized. Hyperinflation was performed for 5 minutes in pressure-controlled ventilation mode, with progressive increases of 5cmH2O until a maximum pressure of 35cmH2O was reached, maintaining positive end expiratory pressure. After 35cmH2O was reached, the inspiratory time and respiratory rate were adjusted so that the inspiratory and expiratory flows reached baseline levels. Measurements of static compliance, total resistance and airway resistance, and peak expiratory flow were evaluated before the technique, immediately after the technique and after aspiration. Two-way analysis of variance for repeated measures was used with Tukey's post hoc test, and p < 0.05 was considered significant. Ventilator hyperinflation increased static compliance, which remained at the same level after aspiration (46.2 ± 14.8 versus 52.0 ± 14.9 versus 52.3 ± 16.0mL/cmH2O; p < 0.001). There was a transient increase in airway resistance (6.6 ± 3.6 versus 8.0 ± 5.5 versus 6.6 ± 3.5cmH2O/Ls-1; p < 0.001) and a transient reduction in peak expiratory flow (32.0 ± 16.0 versus 29.8 ± 14.8 versus 32.1 ± 15.3Lpm; p <0.05) immediately after the technique; these values returned to pretechnique levels after tracheal aspiration. There were no changes in the control condition, nor were hemodynamic alterations observed. Ventilator hyperinflation promoted increased compliance associated with a transient increase in airway resistance and peak expiratory flow, with reduction after aspiration.


Primary percutaneous coronary intervention after out-of-hospital cardiac arrest: patients and outcomes.
The decision to perform primary percutaneous coronary intervention in unconscious patients resuscitated after out-of-hospital cardiac arrest is challenging because of uncertainty regarding the prognosis of recovery of anoxic brain damage and difficulties in interpreting ST segment deviations. In ST elevation myocardial infarction patients after OHCA, primary PCI is generally considered the only option for reperfusion. There are few published studies and no randomized trial has yet been performed in this specific group of patients. To define the demographic, clinical and angiographic characteristics, and the prognosis of STEMI patients undergoing primary PCI after out-of-hospital cardiac arrest. We performed a retrospective analysis of medical records and used the prospectively acquired information from the Rambam Primary Angioplasty Registry (PARR) and the Rambam Intensive Cardiac Care (RICCa) databases. During the period March 1998 to June 2006, 25 STEMI patients (21 men and 4 women, mean age 56 +/- 11years) after OHCA were treated with primary PCI. The location of myocardial infarction was anterior in 13 patients (52%) and non-anterior in 12 (48%). Cardiac arrest was witnessed in 23 patients (92%), but bystander resuscitation was performed in only 2 patients (8%). Eighteen patients (72%) were unconscious on admission, and Glasgow Coma Scale > 5 was noted in 2 patients (8%). Cardiogenic shock on admission was diagnosed in 4 patients (16%). PCI procedure was successful in 22 patients (88%). In-hospital, 30 day, 6 month and 1 year survival was 76%, 76%, 76% and 72%, respectively. In-hospital, 30 day, 6 month and 1 year survival without severe neurological disability was 68%, 68%, 68% and 64%, respectively. In a selected group of STEMI patients after out-of-hospital cardiac arrest, primary PCI can be performed with a high success rate and provides reasonably good results in terms of short and longer term survival.


Senecavirus A.
Senecavirus A (SVA) is the only member of the genus Senecavirus within the family Picornaviridae. This virus was discovered as a serendipitous finding in 2002 (and named Seneca Valley virus 001 [SVV-001]) while cultivating viral vectors in cell culture and has been proposed for use as an oncolytic virus to treat different types of human neoplasia. SVA was found in lesions in pigs affected by porcine idiopathic vesicular disease in Canada and the USA in 2008 and 2012, respectively. In 2014 and 2015, SVA infection was associated with outbreaks of vesicular disease in sows as well as neonatal pig mortality in Brazil and the USA. Phylogenetic analysis of the SVA VP1 indicates the existence of 3 clades of the virus. Clade I contains the historical strain SVV-001, clade II contains USA SVA strains identified between 1988 and 1997, and clade III contains global SVA strains from Brazil, Canada, China, and the USA identified between 2001 and 2015. The aim of this review is to draw the attention of veterinarians and researchers to a recently described infectious clinical-pathologic condition caused by a previously known agent (SVA). Apart from the intrinsic interest in a novel virus infecting pigs and causing economic losses, the major current concern is the similarity of the clinical picture to that of other swine diseases, because one of them-foot and mouth disease-is a World Organization for Animal Health-listed disease. Because the potential association of SVA with disease is rather new, there are still many questions to be resolved.


Intergenerational differences in smoking among West Indian, Haitian, Latin American, and African blacks in the United States.
Due in large part to increased migration from Africa and the Caribbean, black immigrants and their descendants are drastically changing the contours of health disparities among blacks in the United States. While prior studies have examined health variation among black immigrants by region of birth, few have explored the degree of variation in health behaviors, particularly smoking patterns, among first- and second- generation black immigrants by ancestral heritage. Using data from the 1995-2011 waves of the Tobacco Use Supplements of the Current Population Survey (TUS-CPS), we examine variation in current smoking status among first-, second-, and third/higher- generation black immigrants. Specifically, we investigate these differences among all black immigrants and then provide separate analyses for individuals with ancestry from the English-speaking Caribbean (West Indies), Haiti, Latin America, and Africa-the primary sending regions of black immigrants to the United States. We also explore differences in smoking behavior by gender. The results show that, relative to third/higher generation blacks, first-generation black immigrants are less likely to report being current smokers. Within the first-generation, immigrants who migrated after age 13 have a lower probability of smoking relative to those who migrated at or under age 13. Disparities in smoking prevalence among the first-generation by age at migration are largest among black immigrants from Latin America. The results also suggest that second-generation immigrants with two foreign-born parents are generally less likely to smoke than the third/higher generation. We find no statistically significant difference in smoking between second-generation immigrants with mixed nativity parents and the third or higher generation. Among individuals with West Indian, Haitian, Latin American, and African ancestry, the probability of being a current smoker increases with each successive generation. The intergenerational increase in smoking, however, is slower among individuals with African ancestry. Finally, with few exceptions, our results suggest that intergenerational gaps in smoking behavior are larger among women compared to men. As additional sources of data for this population become available, researchers should investigate which ancestral subgroups are driving the favorable smoking patterns for the African origin population.


Systemic delays in the initiation of antiretroviral therapy during pregnancy do not improve outcomes of HIV-positive mothers: a cohort study.
Antiretroviral therapy (ART) initiation in eligible HIV-infected pregnant women is an important intervention to promote maternal and child health. Increasing the duration of ART received before delivery plays a major role in preventing vertical HIV transmission, but pregnant women across Africa experience significant delays in starting ART, partly due the perceived need to deliver ART counseling and patient education before ART initiation. We examined whether delaying ART to provide pre-ART counseling was associated with improved outcomes among HIV-infected women in Cape Town, South Africa. We undertook a retrospective cohort study of 490 HIV-infected pregnant women referred to initiate treatment at an urban ART clinic. At this clinic all patients including pregnant women are screened by a clinician and then undergo three sessions of counseling and patient education prior to starting treatment, commonly introducing delays of 2-4 weeks before ART initiation. Data on viral suppression and retention in care after ART initiation were taken from routine clinic records. A total of 382 women initiated ART before delivery (78%); ART initiation before delivery was associated with earlier gestational age at presentation to the ART service (p < 0.001). The median delay between screening and ART initiation was 21 days (IQR, 14-29 days). Overall, 84.7%, 79.6% and 75.0% of women who were pregnant at the time of ART initiation were retained in care at 4, 8 and 12 months after ART initiation, respectively. Among those retained, 91% were virally suppressed at each follow-up visit. However the delay from screening to ART initiation was not associated with retention in care and/or viral suppression throughout the first year on ART in unadjusted or adjusted analyses. A substantial proportion of eligible pregnant women referred for ART do not begin treatment before delivery in this setting. Among women who do initiate ART, delaying initiation for patient preparation is not associated with improved maternal outcomes. Given the need to maximize the duration of ART before delivery for prevention of mother-to-child HIV transmission, there is an urgent need for new strategies to help expedite ART initiation in eligible pregnant women.


An assemblage of science and home. The gendered lifestyle of Svante Arrhenius and early twentieth-century physical chemistry.
This essay explores the gendered lifestyle of early twentieth-century physics and chemistry and shows how that way of life was produced through linking science and home. In 1905, the Swedish physical chemist Svante Arrhenius married Maja Johansson and established a scientific household at the Nobel Institute for Physical Chemistry in Stockholm. He created a productive context for research in which ideas about marriage and family were pivotal. He also socialized in similar scientific sites abroad. This essay displays how scholars in the international community circulated the gendered lifestyle through frequent travel and by reproducing gendered behavior. Everywhere, husbands and wives were expected to perform distinct duties. Shared performances created loyalties across national divides. The essay thus situates the physical sciences at the turn of the twentieth century in a bourgeois gender ideology. Moreover, it argues that the gendered lifestyle was not external to knowledge making but, rather, foundational to laboratory life. A legitimate and culturally intelligible lifestyle produced the trust and support needed for collaboration. In addition, it enabled access to prestigious facilities for Svante Arrhenius, ultimately securing his position in international physical chemistry.


Kinematic and kinetic analyses of the gait of horses wearing novel legwear for variably limiting extension of the metacarpophalangeal joint.
To investigate the effects of novel legwear designed to limit metacarpophalangeal joint (MCPJ) extension and redirect loading forces from the flexor apparatus through analyses of 2-D kinematic and kinetic data. 6 adult horses without musculoskeletal disease. Horses were subjected to 4 treatments: control (no legwear), inactive legwear (unlimited legwear extension), and active legwear with mild (30°) and moderate (20°) legwear extension limitation. Two-dimensional kinematic data were collected for the right forelimb (FL) during walk and trot and from leading and trailing FLs during canter on a treadmill. Ground reaction force (GRF) data were collected from FLs during overground walk and trot. Peak MCPJ angle and angular velocity were calculated from kinematic data, and peak force and average loading rate were calculated from vertical GRF data during the stance phase of the gait. Interactions between gait and treatment were determined via ANOVA. Interactions between gait and treatment for peak MCPJ angle were significant. Significant reductions in MCPJ angle were noted between the control treatment and legwear with moderate extension limitation for trot and canter (leading and trailing FL) and between inactive legwear and legwear with moderate extension limitation for trot and leading FL during canter. Interactions among peak MCPJ angular velocity, peak vertical GRF, and average loading rate of the vertical GRF showed nonsignificance. Significant reductions in MCPJ extension without significant alterations to peak vertical GRF suggested the legwear's ability to redistribute internal forces. Findings suggested that the legwear may be beneficial for horses rehabilitating from flexor apparatus injuries.


Effects of Sevoflurane on Young Male Adult C57BL/6 Mice Spatial Cognition.
Inhalation anesthetics are reported to affect cognition in both animals and humans. The influence of inhalation anesthetics in learning and memory are contradictory. We therefore investigated the effects of sevoflurane anesthesia with different durations on cognitive performance and the levels of NMDA receptor subunit NR2B, phosphorylated ERK1/2 (p-ERK1/2) and activated caspase3 in mouse hippocampus. We anaesthetized eight-week old male C57BL/6 mice with 2.5% sevoflurane for durations ranging from one to four hours. Non-anaesthetized mice served as controls. Mice exposed to sevoflurane for one to three hours showed improved performance, whereas mice with exposure up to four hours displayed similar behavioral performance as control group. NR2B was increased both at 24h and at two weeks post sevoflurane exposure in all groups. The p-ERK1/2: total ERK1/2 ratio increased at 24h in all anesthesia groups. The ratio remained elevated at two weeks in groups with two- to four-hour exposure. Activated caspase3 was detected elevated at 24h in groups with two- to four-hour exposure. The elevated trend of activated caspase3 was still detectable at two weeks in groups with three- to four-hour exposure. At two weeks post anesthesia, the typical morphology associated with apoptotic cells was observed in the hippocampus of mice exposed to four hours of sevoflurane. Our results indicate that 2.5% sevoflurane exposure for one to three hours improved spatial cognitive performance in young adult mice. The cognitive improvement might be related to the increase of NR2B, the p-ERK1/2: total ERK1/2 ratio in hippocampus. However, exposure to sevoflurane for four hours caused neurotoxicity due to caspase3 activation and apoptosis.


Students' voices on spiritual care at a Higher Education Institution in the Western Cape.
Nurses have a moral obligation to ensure holistic care of patients, inclusive of the spiritual dimension. However, there seems to be a void in the teaching and learning of spiritual care in nursing curricula. Despite the South African Nursing Council being in favour of holistic nursing, there are no measures in place to ensure implementation of spiritual care, hence its practice is not standardised in nursing education in South Africa. Currently, the undergraduate nursing curriculum does not provide clear direction on how spiritual care in nursing should be integrated and the reason for this is not clear. It appears that the lack of professional regulation, difficulties in definition and the personalised nature of spiritual practice are partly responsible for the practice being barely enforced and scarcely practised by students in clinical placements. The aim of the study was to develop a practice theory for teaching-learning of spiritual care in the undergraduate nursing programme. The study objective was to describe and explore the students' experiencs of teaching-learning of spiritual care in the undergraduate nursing programme. A qualitative, explorative, descriptive and contextual design with purposive sampling was used. The sample consisted of undergraduate nursing students at a University in the Western Cape Province. Measures for trustworthiness were applied. The findings indicated a need to provide support, a conducive learning environment and structure for teaching, learning and practice of spiritual care. There is a need for formal education regarding spiritual care in nursing.


Numerical analysis of transmission efficiency for parabolic optical fiber nano-probe.
Theoretical calculations are performed for the transmission efficiencies of parabolic nano-probes with different shapes, based on the finite element method. It shows that the transmittance will fluctuate dramatically with the variation of either wavelength or probe shape, and the efficiency could be rather high even at long wavelengths. Subsequently, we thoroughly investigate this phenomenon and find that these fluctuations are due to the joint effect of light propagating modes and surface plasmon polaritons modes. It indicates that high transmittance can be achieved with the selection of appropriate wavelength and probe structure.


Food availability of glucose and fat, but not fructose, increased in the U.S. between 1970 and 2009: analysis of the USDA food availability data system.
Obesity rates in the United States have risen consistently over the last four decades, increasing from about 13% of the population in 1970 to more than 34% in 2009. Dietary fructose has been blamed as a possible contributor to the obesity increase, although the consumption pattern of fructose and other key nutrients during this 40 year period remains a topic of debate. Therefore, we analyzed the USDA Loss-Adjusted Food Availability Database in combination with the USDA Nutrient Database for Standard Reference (Release 24) to determine whether fructose consumption in the US has increased sufficiently to be a casual factor in the rise in obesity prevalence. Per capita loss-adjusted food availability data for 132 individual food items were compiled and analyzed. Nutrient profiles for each of these foods were used to determine the availability of energy as well as macronutrients and monosaccharides during the years 1970-2009. The percent change in energy from food groups and individual nutrients was determined by using the year 1970 as the baseline and area-under-the-curve analysis of food trends. Our findings indicate that during this 40 year period the percent change in total energy availability increased 10.7%, but that the net change in total fructose availability was 0%. Energy available from total glucose (from all digestible food sources) increased 13.0%. Furthermore, glucose availability was more than 3-times greater than fructose. Energy available from protein, carbohydrate and fat increased 4.7%, 9.8% and 14.6%, respectively. These data suggest that total fructose availability in the US did not increase between 1970 and 2009 and, thus, was unlikely to have been a unique causal factor in the increased obesity prevalence. We conclude that increased total energy intake, due to increased availability of foods providing glucose (primarily as starch in grains) and fat, to be a significant contributor to increased obesity in the US.


Assignment of Emery-Dreifuss muscular dystrophy to the distal region of Xq28: the results of a collaborative study.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humeroperoneal dystrophy associated with cardiomyopathy that is distinct from the Duchenne and Becker forms of X-linked muscular dystrophy. Linkage analysis has assigned EDMD to the terminal region of the human X chromosome long arm. We report here further linkage analysis in two multigenerational EDMD families using seven Xq28 marker loci. Cumulative lod scores suggest that EDMD is approximately 2 cM from DXS52 (lod = 15.67) and very close to the factor VIII (F8C) and the red/green color pigment (R/GCP) loci, with respective lod scores of 9.62 and 10.77, without a single recombinant. Several recombinations between EDMD and three proximal Xq28 markers suggest that the EDMD gene is located in distal Xq28. Multipoint linkage analysis indicates that the odds are 2,000:1 that EDMD lies distal to DXS305. These data substantially refine the ability to perform accurate carrier detection, prenatal diagnosis, and the presymptomatic diagnosis of at-risk males for EDMD by linkage analysis. The positioning of the EDMD locus close to the loci for F8C and R/GCP will assist in future efforts to identify and isolate the disease gene.


Tubal flushing for subfertility.
Establishing the patency of the fallopian tubes is a commonly undertaken diagnostic investigation for women with subfertility. This is usually achieved by flushing contrast medium through the tubes and taking radiographs. However, it has been noted that many women conceive in the first three to six months after the tubal flushing, which has raised the possibility that tubal flushing could also be a treatment for infertility. There has been debate about which contrast medium should be used (water-soluble or oil-soluble media) as this may influence pregnancy rates. To evaluate the effect of flushing fallopian tubes with oil- or water-soluble contrast media on live birth and pregnancy rates in women with subfertility. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials, MEDLINE, EMBASE, Biological Abstracts, trial registers and reference lists of identified articles. The most recent search was conducted in June 2014. Randomised controlled trials (RCTs) comparing tubal flushing with oil-soluble or water-soluble contrast media, or with no treatment, in women with subfertility. Two authors independently selected the trials, assessed risk of bias and extracted data. We contacted study authors for additional information. The overall quality of the evidence was assessed using GRADE methods. Thirteen trials involving 2914 women were included, of whom 2494 were included in the analysis. Oil-soluble contrast media (OSCM) versus no interventionThe OSCM group had a higher rate of live birth (odds ratio (OR) 3.09, 95% CI 1.39 to 6.91, 1 RCT, 158 women, low quality evidence) and ongoing pregnancy (OR 3.59, 95% CI 2.06 to 6.26, 3 RCTs, 382 women, I(2) = 0%, low quality evidence) than women who had no intervention. Our findings suggest that among subfertile women with a 17% chance of an ongoing pregnancy if they have no intervention, the rate will increase to between 29% and 55% if they have tubal flushing with OSCM. Water-soluble contrast media (WSCM) versus no interventionThere was no evidence of a difference between the groups in rates of live birth (OR 1.13, 95% CI 0.67 to 1.91, 1 RCT, 334 women, very low quality evidence) or ongoing pregnancy (OR 1.14, 95% CI 0.71 to 1.84, 1 RCT, 334 women, very low quality evidence). OSCM versus WSCMTwo RCTs reported live birth: one found a higher live birth rate in the oil-soluble group and the other found no evidence of a difference between the groups. These studies were not pooled due to very high heterogeneity (I(2) = 93%). There was no evidence of a difference between the groups in rates of ongoing pregnancy, however there was high heterogeneity (OR 1.44, 95% CI 0.84 to 2.47, 5 RCTs, 1454 women, I(2) = 76%, random-effects model, very low quality evidence). OSCM plus WSCM versus WSCM aloneThere was no evidence of a difference between the groups in rates of live birth (OR 1.06, 95% CI 0.64 to 1.77, 1 RCT, 393 women, very low quality evidence) or ongoing pregnancy (OR 1.23, 95% CI 0.87 to 1.72, 4 RCTs, 633 women, I(2) = 0%, low quality evidence).There was no evidence of a difference between any of the interventions in rates of adverse events, but such events were poorly reported in most studies. The evidence suggests that tubal flushing with oil-soluble contrast media may increase the chance of pregnancy and live birth compared to no intervention. Findings for other comparisons were inconclusive due to inconsistency and lack of statistical power. There was insufficient evidence on adverse events to reach firm conclusions. Further robust randomised controlled trials are needed.


Consultant physician to outpatients.
Analysis of the records of the last 450 outpatients referred to me showed that the basic disorder of at least one in three lay in the psyche, and there was a large emotional element in many of the others. None were put on a waiting list for admission. Not only should physicians be generalists most of the time (whether or not they have a special interest) but most medical problems are best dealt with by the GP. Only occasionally can the physician attach a precise diagnosis to a patient who has been an obscure problem to his GP, and the physician's most important function is to reassure the patient and explain his symptoms. Routine investigations seldom benefit the patient. If there could be a more equitable distribution of GPs of high quality with good back-up facilities fewer general and many fewer specialist physicians would be needed.


Interactions between accumulated copper, bacterial community structure and histamine levels in crayfish meat during storage.
Pollution in aquaculture areas may negatively impact edible species and threaten seafood quality and safety. The aim of this study was to determine the interaction between copper and bacteria in the aquatic habitat and their impact upon crustaceans. Marbled crayfish was chosen as a model of aquatic crustaceans and the influence of metal contamination on bacterial community structure in water used to culture crayfish and in crayfish themselves was investigated. Histamine, an allergen commonly formed by certain groups of bacteria in crustacean edible tissue during storage, was also determined. Copper exposure increased its concentration in crayfish meat by 17.4%, but the copper concentration remained within acceptable food safety limits. Elevated copper levels affected the bacterial community both in the water used to cultivate crayfish and in the marbled crayfish themselves. Cluster analysis of 16S rRNA-gene based microbial community fingerprints revealed that copper impacted the bacterial community in the water and in the crayfish meat. However, copper exposure reduced the formation of histamine in crayfish meat during storage by 66.3%. Copper from the habitat appears to reduce histamine accumulation in crayfish meat during storage by affecting the bacterial community structure of the cultivation water and most likely also in the intestine of the crayfish. From a food safety point of view, copper treatment during the aqua culturing of crustaceans has a positive impact on the postharvest stage.


Virtual reality versus conventional treatment of reaching ability in chronic stroke: clinical feasibility study.
The objective of this study was to evaluate the potential of exercises performed in a 2D video-capture virtual reality (VR) training environment to improve upper limb motor ability in stroke patients compared to those performed in conventional therapy. A small sample randomized control trial, in an outpatient rehabilitation center with 12 patients with chronic stroke, aged 33-80 years, who were randomly allocated to video-capture VR therapy and conventional therapy groups. All patients participated in four clinical evaluation sessions (pre-test 1, pre-test 2, post-test, follow-up) and nine 45-minute intervention sessions over a 3-week period. Main outcomes assessed were Body Structure and Function (impairment: Fugl-Meyer Assessment [FMA]; Composite Spasticity Index [CSI]; Reaching Performance Scale for Stroke), Activity (Box and Blocks; Wolf Motor Function Test [WMFT]), and Participation (Motor Activity Log) levels of the International Classification of Functioning. Improvements occurred in both groups, but more patients in the VR group improved upper limb clinical impairment (FMA, CSI) and activity scores (WMFT) and improvements occurred earlier. Patients in the VR group also reported satisfaction with the novel treatment. The modest advantage of VR over conventional training supports further investigation of the effect of video-capture VR or VR combined with conventional therapy in larger-scale randomized, more intense controlled studies.


Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission.
Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.


The UCP2-related mitochondrial pathway participates in rhein-induced apoptosis in HK-2 cells.
Rhein is one of the main active compounds in total rhubarb anthraquinones (TRAs) that were reported to cause nephrotoxicity. This paper explored the mechanism of how rhein induced apoptosis in human renal proximal tubular epithelial cells (HK-2 cells). In this study, rhein was found to induce apoptosis in HK-2 cells according to the results of annexin V/PI staining assay. The underlying mechanisms were investigated, and the mitochondria-mediated pathway was found to be critical. A series of related biological events were explored, including the disruption of mitochondrial membrane potential (MMP), the decrease of the ATP level, the release of cytochrome c (Cyt-c) from the mitochondrion to the cytosol, and down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, rhein significantly increased the levels of ROS and inhibited the expression of mitochondrial uncoupling protein 2 (UCP2). UCP2 inhibition dramatically boosted oxidative stress and exacerbated rhein-induced apoptosis, whereas co-incubation with an ROS scavenger N-acetylcysteine (NAC) could decrease rhein-induced apoptosis. In conclusion, our results have demonstrated that rhein induced apoptosis in HK-2 cells via the UCP2-related mitochondrial pathway and rhein might be a weak inhibitor of UCP2. Our findings provide new evidence that UCP2 plays an important role in the mitochondrial apoptotic pathway.


Amadori albumin in diabetic nephropathy.
Nonenzymatic glycation of macromolecules in diabetes mellitus (DM) is accelerated due to persistent hyperglycemia. Reducing sugar such as glucose reacts non enzymatically with free €-amino groups of proteins through series of reactions forming Schiff bases. These bases are converted into Amadori product and further into AGEs. Non enzymatic glycation has the potential to alter the biological, structural and functional properties of macromolecules both in vitro and in vivo. Studies have suggested that amadori as well as AGEs are involved in the micro-macro vascular complications in DM, but most studies have focused on the role of AGEs in vascular complications of diabetes. Recently putative AGE-induced patho-physiology has shifted attention from the possible role of amadori-modified proteins, the predominant form of the glycated proteins in the development of the diabetic complications. Human serum albumin (HSA), the most abundant protein in circulation contains 59 lysine and 23 arginine residues that could, in theory be involved in glycation. Albumin has dual nature, first as a marker of intermediate glycation and second as a causative agent of the damage of tissues. Among the blood proteins, hemoglobin and albumin are the most common proteins that are glycated. HSA with a shorter half life than RBC, appears to be an alternative marker of glycemic control as it can indicate blood glucose status over a short period (2-3 weeks) and being unaffected by RBCs life span and variant haemoglobin, anemia etc which however, affect HbA1c. On the other hand, Amadori albumin may accumulate in the body tissues of the diabetic patients and participate in secondary complications. Amadori-albumin has potential role in diabetic glomerulosclerosis due to long term hyperglycaemia and plays an important role in the pathogenesis of diabetic nephropathy. This review is an approach to compile both the nature of glycated albumin as a damaging agent of tissues and as an intermediate diagnostic marker and its potential role in diabetic nephropathy.


Host structural carbohydrate induces vector transmission of a bacterial plant pathogen.
Many insect-borne pathogens have complex life histories because they must colonize both hosts and vectors for successful dissemination. In addition, the transition from host to vector environments may require changes in gene expression before the pathogen's departure from the host. Xylella fastidiosa is a xylem-limited plant-pathogenic bacterium transmitted by leafhopper vectors that causes diseases in a number of economically important plants. We hypothesized that factors of host origin, such as plant structural polysaccharides, are important in regulating X. fastidiosa gene expression and mediating vector transmission of this pathogen. The addition of pectin and glucan to a simple defined medium resulted in dramatic changes in X. fastidiosa's phenotype and gene-expression profile. Cells grown in the presence of pectin became more adhesive than in other media tested. In addition, the presence of pectin and glucan in media resulted in significant changes in the expression of several genes previously identified as important for X. fastidiosa's pathogenicity in plants. Furthermore, vector transmission of X. fastidiosa was induced in the presence of both polysaccharides. Our data show that host structural polysaccharides mediate gene regulation in X. fastidiosa, which results in phenotypic changes required for vector transmission. A better understanding of how vector-borne pathogens transition from host to vector, and vice versa, may lead to previously undiscovered disease-control strategies.


Diagnosis and classification of reactive arthritis.
Reactive arthritis is a form of seronegative spondyloarthritis clinically associated with inflammatory back pain, additive or migratory oligoarthritis, and extra-articular symptoms that typically follow a gastrointestinal or urogenital infection by a minimum of 1 to a maximum of 3-6 weeks. Once arthritis is observed, however, microbial tests and blood or synovial fluid cultures are negative, and only serum antibodies are detected. Reactive arthritis commonly affects young adults, most frequently white and carrying the HLA-B27 allele. The genetic susceptibility appears as necessary with only 1-15% of cases of infection developing reactive arthritis. Clinical symptoms are different from septic arthritis which manifests with fever, systemic signs of infection, and monoarthritis. The presence of large joint oligoarthritis, urogenital tract infection, and uveitis characterizes Reiter's syndrome as a clinical subtype. Ocular, skin, and heart involvement are not uncommon and may be largely variable in severity. Diagnostic criteria are based on the ACR guidelines and include rheumatological signs along with a proof of infection.


Hyperinnervation of skeletal muscle fibers: dependence on muscle activity.
After the motor nerve to the rat soleus muscle was blocked reversibly by local anesthesia, individual muscle fibers became innervated by a transplanted motor nerve without losing their original innervation. Such cross-innervation of the denervated soleus muscle by the same foreign nerve was largely reduced by direct electrical stimulation of the muscle. The results demonstrate the importance of muscle activity for synapse formation by a foreign motor nerve.


Magnetism-tuning strategies for graphene oxide based on magnetic oligoacene oxide patches model.
Graphene oxide (GO) has wide application potential owing to its 2D structure and diverse modification sites for various targeted uses. The introduction of magnetism into GO structures has further advanced the controllability of the application of GO materials. Herein, the concept of modular design and modeling was applied to tune the magnetism of GO. To obtain desirable magnetic properties, diradical-structured GO patches were formed by the introduction of two functional groups to break the Kekule structure of the benzene ring. In these diradical GO patches, the energy of the triplet state was lower than those of the open-shell broken-symmetry singlet state and closed-shell singlet state. To create such multi-radical patches, a practical approach is to determine a substantial spatial separation of the α and β spin densities in the molecule. Thus, systematic design strategies and tests were evaluated. The first strategy was extending the distance between the distribution center of the α and β spin densities; the second was controlling the delocalization directions of the α and β electrons; the third was controlling the delocalization extension of the α and β electrons by oxidative modification, and finally introducing multi-radical structures into the molecular system and controlling the position of each radical. Herein, successful molecular models with a large magnetic coupling constant (∼3600 cm-1) were obtained. This study paves the way to explore ferromagnetic MGO guided by theoretical study, which may become reality soon.


Improving quality and safety in nursing homes and home care: the study protocol of a mixed-methods research design to implement a leadership intervention.
Nursing homes and home care face challenges across different countries as people are living longer, often with chronic conditions. There is a lack of knowledge regarding implementation and impact of quality and safety interventions as most research evidence so far is generated in hospitals. Additionally, there is a lack of effective leadership tools for quality and safety improvement work in this context. The aim of the 'Improving Quality and Safety in Primary Care-Implementing a Leadership Intervention in Nursing Homes and Homecare' (SAFE-LEAD) study is to develop and evaluate a research-based leadership guide for managers to increase quality and safety competence. The project applies a mixed-methods design and explores the implications of the leadership guide on managers' and staffs' knowledge, attitudes and practices. Four nursing homes and four home care services from different Norwegian municipalities will participate in the intervention. Surveys, process evaluation (interviews, observations) and document analyses will be conducted to evaluate the implementation and impact of the leadership intervention. A comparative study of Norway and the Netherlands will establish knowledge of the context dependency of the intervention. The study is approved by the Norwegian Centre for Research Data (2017/52324 and 54855). The results will be disseminated through scientific articles, two PhD dissertations, an anthology, presentations at national and international conferences, and in social media, newsletters and in the press. The results will generate knowledge to inform leadership practices in nursing homes and home care. Moreover, the study will build new theory on leadership interventions and the role of contextual factors in nursing homes and home care.


Expression and Function of Transient Receptor Potential Ankyrin 1 Ion Channels in the Caudal Nucleus of the Solitary Tract.
The nucleus of the solitary tract (NTS) receives visceral information via the solitary tract (ST) that comprises the sensory components of the cranial nerves VII, IX and X. The Transient Receptor Potential Ankyrin 1 (TRPA1) ion channels are non-selective cation channels that are expressed primarily in pain-related sensory neurons and nerve fibers. Thus, TRPA1 expressed in the primary sensory afferents may modulate the function of second order NTS neurons. This hypothesis was tested and confirmed in the present study using acute brainstem slices and caudal NTS neurons by RT-PCR, immunostaining and patch-clamp electrophysiology. The expression of TRPA1 was detected in presynaptic locations, but not the somata of caudal NTS neurons that did not express TRPA1 mRNA or proteins. Moreover, caudal NTS neurons did not show somatodendritic responsiveness to TRPA1 agonists, while TRPA1 immunostaining was detected only in the afferent fibers. Electrophysiological recordings detected activation of presynaptic TRPA1 in glutamatergic terminals synapsing on caudal NTS neurons evidenced by the enhanced glutamatergic synaptic neurotransmission in the presence of TRPA1 agonists. The requirement of TRPA1 for modulation of spontaneous synaptic activity was confirmed using TRPA1 knockout mice where TRPA1 agonists failed to alter synaptic efficacy. Thus, this study provides the first evidence of the TRPA1-dependent modulation of the primary afferent inputs to the caudal NTS. These results suggest that the second order caudal NTS neurons act as a TRPA1-dependent interface for visceral noxious-innocuous integration at the level of the caudal brainstem.


Imbalanced shift of cytokine expression between T helper 1 and T helper 2 (Th1/Th2) in intestinal mucosa of patients with post-infectious irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a common functional bowel disorder. The post-infectious IBS (PI-IBS) occurs in IBS patients with a history of intestinal infection preceding the onset of symptoms. However, the underlying cause of PI-IBS is not fully understood, and the purpose of this study was to investigate the immune regulatory mechanism of PI-IBS. Participants enrolled in this study were divided into three groups including PI-IBS patients (n = 20), IBS patients without a history of infection (non-PI-IBS, n = 18), and healthy controls (n = 20). The expression levels of the Th1-derived cytokines IFN-γ and IL-12, and the Th2-derived cytokines IL-4 and IL-10 in the mucosal specimens, and in the ascending colon, the descending colon, and the rectal segments were measured by RT-PCR and western blot. The IFN-γ mRNA levels in the intestinal mucosa were significantly higher in the PI-IBS group than in the non-PI-IBS or control group (both P < 0.05), but there was no difference between the non-PI-IBS and control groups. A trend toward IFN-γ protein upregulation was found in the PI-IBS group, while the IL-12 and IL-4 mRNA and protein levels were not different between any groups. The IL-10 mRNA and protein levels in the PI-IBS group were both significantly lower than in the non-PI-IBS or control groups (P < 0.05, respectively), but there was no difference between the non-PI-IBS and control groups. There were no differences in the cytokine mRNA and protein levels among the ascending colon, the descending colon, and the rectum of all groups. An increase in IFN-γ levels and a decrease in IL-10 levels were found in the intestinal mucosa of PI-IBS patients, suggesting that the infection may affect the Th1/Th2 balance. Thus, the dysregulation of the immune response is likely an important cause of IBS.


Growth hormone assays: current methodologies and their limitations.
Measurement of circulating growth hormone (GH) concentrations is essential in diagnosis of either GH deficiency or GH excess. The invention of immunoassays for the measurement of peptide hormones was a major breakthrough, enabling the routine analysis of GH concentrations in larger series of samples. Over the last few decades, measurement technology has evolved from less sensitive, mainly radioactive assays based on polyclonal antisera to the latest generations of highly sensitive chemiluminescence methods employing monoclonal antibodies. Unfortunately, the development of newer assays did not lead to better agreement among the results obtained by different assay methods. On the contrary, the differences tended to increase when monoclonal antibody based assays became more popular. The actual value reported for the GH concentration in a specific patient's sample still mainly depends on the method used by the respective laboratory, limiting the applicability of international consensus guidelines in clinical practice. The heterogeneity of the analyte itself, the availability of different reference preparations for calibration and the interference from matrix components such as GH binding protein are among the reasons why standardizing GH assays is difficult. An additional challenge arose from the availability of a GH receptor antagonist for the treatment of acromegaly, which is basically a mutated form of GH and therefore interferes in many GH assays. This review provides an overview on GH assays used in clinical practice, their limitations and the potential next steps towards standardization.


Angiostrongylus vasorum from South America and Europe represent distinct lineages.
Angiostrongylus vasorum is a nematode parasite of sylvan and domestic species of the family Canidae. It has a broad but patchy distribution worldwide, and there is evidence for geographical spread and increasing incidence of infection in recent years. While historically Angiostrongylus-like nematodes identified in dogs and foxes have been described as A. vasorum in Europe and Angiocaulus raillieti in South America, more recent taxonomic revision has amalgamated these into a single species, A. vasorum. Here we report, for the first time, the molecular characterization of isolates of A. vasorum from Germany, Portugal, Denmark and the United Kingdom on the basis of the mitochondrial COI gene and the second ribosomal internal transcribed spacer. When compared with isolates from Brazil, sequence analysis revealed 2 distinct genotypes. Estimated rates of evolution based on COI sequences for both nematode and host are consistent with the hypothesis that the presence of A. vasorum in South America is a result of an ancient evolutionary event. Angiostrongylus vasorum in South America potentially represents a separate species to that observed in Europe.


Methylation of imprinted IGF2 regions is associated with total, visceral, and hepatic adiposity in postmenopausal women.
Excess body fat, especially intra-abdominal fat, is a leading risk factor for metabolic diseases. Differentially methylated regions (DMRs) of two imprinted genes, insulin-like growth factor 2 (IGF2) and H19, have been associated with obesity due to their important roles in regulating body composition, but have not been examined in relation to intra-abdominal fat depots. Total body fat from whole-body dual energy X-ray absorptiometry and visceral and liver fat contents from abdominal magnetic resonance imaging in 48 healthy women aged 60-65 years (of White or Japanese ancestry) were each regressed on circulating leukocyte DNA methylation levels of IGF2 (at DMR0, DMR2a, and DMR2b) and H19 (at CTCF3) as assessed by pyrosequencing, while adjusting for age and race/ethnicity. Total fat mass was inversely associated with methylation levels of IGF2 DMR2b (P = 0.016). Total fat-adjusted visceral fat area (P = 0.062) and percent visceral fat measured at L4-L5 (P = 0.045) were associated with higher methylation levels of IGF2 DMR2b. Both total fat-adjusted percent liver fat (P = 0.039) and the presence of fatty liver (P = 0.015) were positively associated with IGF2 DMR2a methylation. Methylation levels of H19 CTCF3 were not associated with overall or intra/abdominal adiposity. The findings indicate that methylation levels of IGF2 DMR regions in leukocytes are associated with total body fat and with fat distribution in the viscera and liver independently of total adiposity.


A unique mode of microtubule stabilization induced by peloruside A.
Microtubules are significant therapeutic targets for the treatment of cancer, where suppression of microtubule dynamicity by drugs such as paclitaxel forms the basis of clinical efficacy. Peloruside A, a macrolide isolated from New Zealand marine sponge Mycale hentscheli, is a microtubule-stabilizing agent that synergizes with taxoid drugs through a unique site and is an attractive lead compound in the development of combination therapies. We report here unique allosteric properties of microtubule stabilization via peloruside A and present a structural model of the peloruside-binding site. Using a strategy involving comparative hydrogen-deuterium exchange mass spectrometry of different microtubule-stabilizing agents, we suggest that taxoid-site ligands epothilone A and docetaxel stabilize microtubules primarily through improved longitudinal interactions centered on the interdimer interface, with no observable contributions from lateral interactions between protofilaments. The mode by which peloruside A achieves microtubule stabilization also involves the interdimer interface, but includes contributions from the alpha/beta-tubulin intradimer interface and protofilament contacts, both in the form of destabilizations. Using data-directed molecular docking simulations, we propose that peloruside A binds within a pocket on the exterior of beta-tubulin at a previously unknown ligand site, rather than on alpha-tubulin as suggested in earlier studies.


Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data.
A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA. In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell-mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model. Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary.


Splicing in the human brain.
It has become increasingly clear over the past decade that RNA has important functions in human cells beyond its role as an intermediate translator of DNA to protein. It is now known that RNA plays highly specific roles in pathways involved in regulatory, structural, and catalytic functions. The complexity of RNA production and regulation has become evident with the advent of high-throughput methods to study the transcriptome. Deep sequencing has revealed an enormous diversity of RNA types and transcript isoforms in human cells. The transcriptome of the human brain is particularly interesting as it contains more expressed genes than other tissues and also displays an extreme diversity of transcript isoforms, indicating that highly complex regulatory pathways are present in the brain. Several of these regulatory proteins are now identified, including RNA-binding proteins that are neuron specific. RNA-binding proteins also play important roles in regulating the splicing process and the temporal and spatial isoform production. While significant progress has been made in understanding the human transcriptome, many questions still remain regarding the basic mechanisms of splicing and subcellular localization of RNA. A long-standing question is to what extent the splicing of pre-mRNA is cotranscriptional and posttranscriptional, respectively. Recent data, including studies of the human brain, indicate that splicing is primarily cotranscriptional in human cells. This chapter describes the current understanding of splicing and splicing regulation in the human brain and discusses the recent global sequence-based analyses of transcription and splicing.


A 3-year follow-up of participation in peer support groups after a cardiac event.
Secondary prevention is an important component of a structured rehabilitation programme following a cardiac event. Comprehensive programmes have been developed in many European countries, the vast majority of which are hospital based. In Sweden, all patients with cardiac disease are also given the opportunity to participate in secondary prevention activities arranged by the National Association for Heart and Lung Patients [The Heart & Lung School (HL)]. The aim of this 3-year longitudinal study was to compare persons who attended the HL after a cardiac event and those who declined participation, with regard to health aspects, life situation, social network and support, clinical data, rehospitalisation and mortality. Totally 220 patients were included in the study. The patients were asked to fill in a questionnaire on four occasions, in addition to visiting a health care center for physical examination. After 3 years, 160 persons were still participating, 35 of whom attended the HL. The results show that persons who participated in the HL exercised more regularly, smoked less and had a denser network as well as more social support from nonfamily members than the comparison groups. This study contributes to increased knowledge among healthcare professionals, politicians and decision makers about peer support groups as a support strategy after a cardiac event.


Bond Graph Modeling of Mechanical Circulatory Support Device-Cardiovascular System Interactions.
Though mechanical circulatory support (MCS) devices, such as ventricular assist devices and total artificial hearts (TAH), provide heart failure patients with bridges to heart transplantation or are alternatives to transplantation, device performance, and corresponding control strategies are often difficult to evaluate. Difficulties arise due to the complex interaction of multiple domains-i.e., biological, hydraulic, hemodynamics, electromechanical, system dynamics, and controls. In an attempt to organize, integrate and clarify these interactions, a technique often used in hydraulic pump design and robotics, called "bond graph modeling," is applied to describe the performance and functionality of MCS devices and the interaction between the cardiovascular (CV) system and the MCS device. This technical brief demonstrates the advantages of this tool in formulating a model for the systemic circulation interacting with the left side of a TAH, adopting the fundamental structure of either a hydraulic mechanism (i.e., AbioCor/Carmat) or a pneumatic mechanism (i.e., SynCardia), combined with a systemic circulation loop. The model captures the dynamics of the membrane, the hydraulic source or pneumatic source, and the systemic circulation. This multidisciplinary cross-pollination of an analytical tool from the field of dynamic systems may provide important insight to further aid and improve the design and control of future MCS systems.


[The tracing of brain tissue and 3-D imaging display CT image application: 3-D recursive tracing].
The size and the shape of brain tissue offer lots of information for clinical diagnosis and treatment. The commercial imaging systems, such as x-ray computer tomography (CT) and magnetic resonant image (MRI), always display only two dimensional (2-D) image, which makes quantitative diagnosis of the variation of brain tissue very difficult. Furthermore, some tissue may be connected through little vessels, which is also difficult to identify using discrete 2-D image. In this study, we processed CT image data using an general purpose IBM personal computer. A new three dimensional (3-D) recursive tracing algorithm was proposed. This new algorithm can automatically extract the image of brain tissue in each 2-D image. The information obtained was therefore used to reconstruct 3-D image. This system allows user to observe 3-D size and shape of brain tissue from arbitrary view. Such 3-D image can also be used to calculate the volume of tissue. Using overlay projecting method, it can display skin, bone, brain tissue and gray material at the same time. Such display method accurately shows the relative position of each tissue and offer physicians important information for diagnosis and treatment.


Identification and characterization of receptor-specific peptides for siRNA delivery.
Tumor-targeted delivery of siRNA remains a major barrier in fully realizing the therapeutic potential of RNA interference. While cell-penetrating peptides (CPP) are promising siRNA carrier candidates, they are universal internalizers that lack cell-type specificity. Herein, we design and screen a library of tandem tumor-targeting and cell-penetrating peptides that condense siRNA into stable nanocomplexes for cell type-specific siRNA delivery. Through physiochemical and biological characterization, we identify a subset of the nanocomplex library of that are taken up by cells via endocytosis, trigger endosomal escape and unpacking of the carrier, and ultimately deliver siRNA to the cytosol in a receptor-specific fashion. To better understand the structure-activity relationships that govern receptor-specific siRNA delivery, we employ computational regression analysis and identify a set of key convergent structural properties, namely the valence of the targeting ligand and the charge of the peptide, that help transform ubiquitously internalizing cell-penetrating peptides into cell type-specific siRNA delivery systems.


Exploring prostate cancer survivors' self-management behaviours and examining the mechanism effect that links coping and social support to health-related quality of life, anxiety and depression: a prospective longitudinal study.
Little is known about the influence of psycho-social factors on health-related quality of life (HRQoL), anxiety and depression in men affected by prostate cancer. Developing an understanding in this area can help to identify men who are at high risk of inadequate support and suggest directions for appropriately targeted interventions. Moreover, little is known about how men affected by prostate cancer mobilise social support in their self-management behaviours over time. This is the first study to test the effects of coping and social support on HRQoL and emotional outcome, and assessed the self-management behaviours of men affected by prostate cancer overtime. The study population was 74 prostate cancer patients with a mean age of 67.3 (SD 7.9) years and mixed treatment modalities. The EORTC QLQ-C30, PR25 and HADS were used to assess the dependant variables before treatment and at six months follow-up. Statistical analysis was performed in SPSS version 17.0 using parametric tests and non-parametric tests. A significant decline in quality of life was observed at 6 months post diagnosis (p < 0.001). Perceived social support before radical treatment was the most important social support construct that predicted better global quality of life and less depression at six months, explaining approximately 30% of the variance. Despite men's self-management efforts and use of social support overtime, self-management self-efficacy significantly reduced at six months (p < 0.05). These findings provide support towards the development of a psycho-social intervention study to improve quality of life, self-management self-efficacy and improve patients' symptom management.


Definition of an HPV18/45 cross-reactive human T-cell epitope after DNA immunisation of HLA-A2/KB transgenic mice.
Although human papillomavirus (HPV) types 16 and 18 are the most common types associated with cervical cancer worldwide, other related HPV types such as HPV 35, 45 and 58 have significant prevalence in geographically distinct populations. For development of global prophylactic and therapeutic vaccine strategies, it is important to study immune responses against these viruses and to define the degree of cross-reactivity between related HPV types. To investigate the potential for T cell cross-reactivity after vaccination, HLA-A2/Kb transgenic mice were immunised with DNA plasmid constructs containing HPV18 and 45 E6 and E7. Splenocytes from immunised mice were tested in direct ELIspot assays against overlapping pools of HPV 18 peptides. Immunisation with either HPV18 or HPV45 E6 DNA produced dominant T cell responses against an epitope (KCIDFYSRI) that was shared between HPV18 and HPV45. This peptide was shown to bind to HLA-A*0201 but not Db or Kb molecules on the cell surface. Furthermore this peptide was shown to be immunogenic in vitro to human T cells from 2 out of 3 HLA-A2+ healthy donors. Collectively, these results demonstrate that HPV 18 and 45 E6 DNA vaccines are immunogenic in mice and demonstrate that cross-reactive T cell responses against closely related HPV types can be induced in vivo. The use of the HLA-A2/Kb transgenic mice allowed definition of an HLA-A*0201 binding peptide epitope that would have been rejected on the basis of predicted major histocompatibility complex binding affinity.


Asymmetric Regulation of Peripheral Genes by Two Transcriptional Regulatory Networks.
Transcriptional regulatory network (TRN) reconstitution and deconstruction occur simultaneously during reprogramming; however, it remains unclear how the starting and targeting TRNs regulate the induction and suppression of peripheral genes. Here we analyzed the regulation using direct cell reprogramming from human dermal fibroblasts to monocytes as the platform. We simultaneously deconstructed fibroblastic TRN and reconstituted monocytic TRN; monocytic and fibroblastic gene expression were analyzed in comparison with that of fibroblastic TRN deconstruction only or monocytic TRN reconstitution only. Global gene expression analysis showed cross-regulation of TRNs. Detailed analysis revealed that knocking down fibroblastic TRN positively affected half of the upregulated monocytic genes, indicating that intrinsic fibroblastic TRN interfered with the expression of induced genes. In contrast, reconstitution of monocytic TRN showed neutral effects on the majority of fibroblastic gene downregulation. This study provides an explicit example that demonstrates how two networks together regulate gene expression during cell reprogramming processes and contributes to the elaborate exploration of TRNs.


A genetic study of bipolar affective disorder.
A group of 46 bipolar probands and their first degree relatives were studied. A high rate of affective disorder (19.6 per cent) was found, including both unipolar (13.2 percent) and bipolar (6.4 per cent) types, with females predominating (3 : 1). The presence of four fatherson pairs suffering from affective disorder made the hypothesis of X-linked dominance untenable. Results compatible with polygenic inheritance were found, using both Slater's and Falconer's methods. There was no evidence for assortative mating or for increased total number of females (both well and ill) among first degree relatives. The probands and affectively ill first degree relatives who have died show an alarmingly high rate of suicide (46 per cent). Other forms of mental disorder, including alcoholism, were no more common than in the rest of the community.


Quantification of the Morphological Signature of Roping Based on Multiscale Analysis and Autocorrelation Function Description.
Roping or ridging is a visual defect affecting the surface of ferritic stainless steels, assessed using visual inspection of the surfaces. The aim of this study was to quantify the morphological signature of roping to link roughness results with five levels of roping identified with visual inspection. First, the multiscale analysis of roughness showed that the texture aspect ratio Str computed with a low-pass filter of 32 µm gave a clear separation between the acceptable levels of roping and the non-acceptable levels (rejected sheets). To obtain a gradation description of roping instead of a binary description, a methodology based on the use of the autocorrelation function was created. It consisted of several steps: a low-pass filtering of the autocorrelation function at 150 µm, the segmentation of the autocorrelation into four stabilized portions, and finally, the computation of isotropy and the root-mean-square roughness Sq on the obtained quarters of function. The use of the isotropy combined with the root-mean-square roughness Sq led to a clear separation of the five levels of roping: the acceptable levels of roping corresponded to strong isotropy (values larger than 10%) coupled with low root-mean-square roughness Sq. Both methodologies can be used to quantitatively describe surface morphology of roping in order to improve our understanding of the roping phenomenon.


A new assay for measuring chromosome instability (CIN) and identification of drugs that elevate CIN in cancer cells.
Aneuploidy is a feature of most cancer cells that is often accompanied by an elevated rate of chromosome mis-segregation termed chromosome instability (CIN). While CIN can act as a driver of cancer genome evolution and tumor progression, recent findings point to the existence of a threshold level beyond which CIN becomes a barrier to tumor growth and therefore can be exploited therapeutically. Drugs known to increase CIN beyond the therapeutic threshold are currently few in number, and the clinical promise of targeting the CIN phenotype warrants new screening efforts. However, none of the existing methods, including the in vitro micronuclei (MNi) assay, developed to quantify CIN, is entirely satisfactory. We have developed a new assay for measuring CIN. This quantitative assay for chromosome mis-segregation is based on the use of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Thus, cells that inherit the HAC display green fluorescence, while cells lacking the HAC do not. This allows the measurement of HAC loss rate by routine flow cytometry. Using the HAC-based chromosome loss assay, we have analyzed several well-known anti-mitotic, spindle-targeting compounds, all of which have been reported to induce micronuclei formation and chromosome loss. For each drug, the rate of HAC loss was accurately measured by flow cytometry as a proportion of non-fluorescent cells in the cell population which was verified by FISH analysis. Based on our estimates, despite their similar cytotoxicity, the analyzed drugs affect the rates of HAC mis-segregation during mitotic divisions differently. The highest rate of HAC mis-segregation was observed for the microtubule-stabilizing drugs, taxol and peloruside A. Thus, this new and simple assay allows for a quick and efficient screen of hundreds of drugs to identify those affecting chromosome mis-segregation. It also allows ranking of compounds with the same or similar mechanism of action based on their effect on the rate of chromosome loss. The identification of new compounds that increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target the CIN phenotype in cancer cells.


[The intrahepatic portosystemic shunt. Initial clinical experiences with patients with liver cirrhosis].
A new nonoperative catheter technique to perform an intrahepatic portosystemic shunt by transjugular approach was applied to ten patients with recurrent bleeding from oesophageal and fundal varices. Therefore a balloon-expandable stent was placed between a portal vein and a hepatic vein. Implantation of the stent was successful in seven of the ten patients. Two of these seven patients died 10 and 11 days, respectively, after the procedure, one of them in consequence of respiratory failure, the other due to an uncontrollable bleeding from the site of the percutaneous transhepatic puncture because of a marked clotting disorder. The intrahepatic shunt construction led to a mean reduction of the pressure gradient between portal and hepatic vein of 40%. No recurrence of variceal haemorrhage occurred during the average follow-up time of 5.6 months (3-9 months). One patient developed several episodes of portosystemic encephalopathy. The transjugular intrahepatic portosystemic shunt is effective in the treatment of portal hypertension and might become an alternative to shunt surgery.


Multicenter Clinical Evaluation of the Revogene Strep A Molecular Assay for Detection of Streptococcus pyogenes from Throat Swab Specimens.
Group A streptococcus (GAS) species cause bacterial pharyngitis in both adults and children. Early and accurate diagnosis of GAS is important for appropriate antibiotic therapy to prevent GAS sequalae. The Revogene Strep A molecular assay (Meridian Bioscience Canada Inc, Quebec City, QC, Canada) is an automated real-time PCR assay for GAS detection from throat swab specimens within approximately 70 min. This multicenter prospective study evaluated the performance of the Revogene Strep A molecular assay compared to that of bacterial culture. Dual throat swab specimens in either liquid Amies or Stuart medium were collected from eligible subjects (pediatric population and adults) enrolled across 7 sites (USA and Canada). Revogene Strep A and reference testing was performed within 7 days and 48 h of sample collection, respectively. Of the 604 evaluable specimens, GAS was detected in 154 (25.5%) samples by the reference method and in 175 (29%) samples by the Revogene Strep A assay. Revogene Strep A assay sensitivity and specificity were reported to be 98.1% (95% confidence interval [CI], 94.4 to 99.3) and 94.7% (95% CI, 92.2 to 96.4), respectively. The positive predictive value was 86.3% (95% CI, 80.4 to 90.6), negative predictive value was 99.3% (95% CI, 98.0 to 99.8) with a 1.0% invalid rate. Discrepant analysis with alternative PCR/bidirectional sequencing was performed for 24 false-positive (FP) and 3 false-negative (FN) specimens. Concordant results were reported for 17 (FP only) of 27 discordant specimens. The Revogene Strep A assay had high sensitivity and specificity for GAS detection and provides a faster alternative for GAS diagnosis.


Label-free detection of rare circulating tumor cells by image analysis and machine learning.
Detection and characterization of rare circulating tumor cells (CTCs) in patients' blood is important for the diagnosis and monitoring of cancer. The traditional way of counting CTCs via fluorescent images requires a series of tedious experimental procedures and often impacts the viability of cells. Here we present a method for label-free detection of CTCs from patient blood samples, by taking advantage of data analysis of bright field microscopy images. The approach uses the convolutional neural network, a powerful image classification and machine learning algorithm to perform label-free classification of cells detected in microscopic images of patient blood samples containing white blood cells and CTCs. It requires minimal data pre-processing and has an easy experimental setup. Through our experiments, we show that our method can achieve high accuracy on the identification of rare CTCs without the need for advanced devices or expert users, thus providing a faster and simpler way for counting and identifying CTCs. With more data becoming available in the future, the machine learning model can be further improved and can serve as an accurate and easy-to-use tool for CTC analysis.


Leukemia inhibitory factor activates cardiac L-Type Ca2+ channels via phosphorylation of serine 1829 in the rabbit Cav1.2 subunit.
We have previously reported that leukemia inhibitory factor (LIF) gradually increased cardiac L-type Ca2+ channel current (I(CaL)), which peaked at 15 minutes in both adult and neonatal rat cardiomyocytes, and this increase was blocked by the mitogen-activated protein kinase kinase inhibitor PD98059. This study investigated the molecular basis of LIF-induced augmentation of I(CaL) in rodent cardiomyocytes. LIF induced phosphorylation of a serine residue in the alpha(1c) subunit (Ca(v)1.2) of L-type Ca2+ channels in cultured rat cardiomyocytes, and this phosphorylation was inhibited by PD98059. When constructs encoding either a wild-type or a carboxyl-terminal-truncated rabbit Ca(v)1.2 subunit were transfected into HEK293 cells, LIF induced phosphorylation of the resultant wild-type protein but not the mutant protein. Cotransfection of constitutively active mitogen-activated protein kinase kinase also resulted in phosphorylation of the Ca(v)1.2 subunit in the absence of LIF stimulation. In in-gel kinase assays, extracellular signal-regulated kinase phosphorylated a glutathione S-transferase fusion protein of the carboxyl-terminal region of Ca(v)1.2 (residues 1700 through 1923), which contains the consensus sequence Pro-Leu-Ser-Pro. A point mutation within this consensus sequence, which results in a substitution of alanine for serine at residue 1829 (S1829A), was sufficient to abolish the LIF-induced phosphorylation. LIF increased I(CaL) in HEK cells transfected with wild-type Ca(v)1.2 but not with the mutated version. These results provide direct evidence that LIF phosphorylates the serine residue at position 1829 of the Ca(v)1.2 subunit via the actions of extracellular signal-regulated kinase and that this phosphorylation increases I(CaL) in cardiomyocytes.


Health status and physical fitness of mines rescue brigadesmen.
The aim of the study was to assess health status of regular and part-time mines rescue brigadesmen. A group of 685 mines rescue brigadesmen was examined within the preventive testing - a basic internal, biochemistry and anthropometric examination, physical fitness testing. The average age of the subjects was 41.96±7.18 years, the average exposure in mining was 20±8.1 years, out of that 11.95±7.85 years as mines rescue brigadesmen. Elevated levels of total serum cholesterol (T-CH) and low-density lipoprotein cholesterol (LDL-CH) were found in over 1/2 of the subjects. Systolic hypertension (systolic blood pressure (SBP) ≥ 140 mm Hg) was confirmed in 34%, overweight (body mass index (BMI) ≥ 25) in 62.3% and obesity (BMI ≥ 30) in 20.4% of the examined mines rescue brigadesmen. The metabolic syndrome was found in 15.2% of persons. The highest physical fitness was found in mines rescue brigadesmen and the lowest in mine officers. Limit values of maximum oxygen uptake (VO2 max/kg) determined by the management of the mine rescue station were not reached by every 3rd of all mines rescue brigadesmen. Compared with the control group of the Czech and Slovak population, the rescuers are taller, have greater BMI, higher percentage of body fat in all age categories and proportionally to that they achieve a higher maximum minute oxygen uptake; however, in relative values per kg of body weight their physical fitness is practically the same as that of the controls. The prevalence of risk factors of cardiovascular diseases and VO2 max/kg in the group of the mines rescue brigadesmen is comparable with that in the general untrained Czech population.


Assessment of Shared Decision-making for Stroke Prevention in Patients With Atrial Fibrillation: A Randomized Clinical Trial.
Shared decision-making (SDM) about anticoagulant treatment in patients with atrial fibrillation (AF) is widely recommended but its effectiveness is unclear. To assess the extent to which the use of an SDM tool affects the quality of SDM and anticoagulant treatment decisions in at-risk patients with AF. This encounter-randomized trial recruited patients with nonvalvular AF who were considering starting or reviewing anticoagulant treatment and their clinicians at academic, community, and safety-net medical centers between January 30, 2017 and June 27, 2019. Encounters were randomized to either the standard care arm or care that included the use of an SDM tool (intervention arm). Data were analyzed from August 1 to November 30, 2019. Standard care or care using the Anticoagulation Choice Shared Decision Making tool (which presents individualized risk estimates and compares anticoagulant treatment options across issues of importance to patients) during the clinical encounter. Quality of SDM (which included quality of communication, patient knowledge about AF and anticoagulant treatment, accuracy of patient estimates of their own stroke risk [within 30% of their estimate], decisional conflict, and satisfaction), decisions made during the encounter, duration of the encounter, and clinician involvement of patients in the SDM process. The clinical trial enrolled 922 patients (559 men [60.6%]; mean [SD] age, 71 [11] years) and 244 clinicians. A total of 463 patients were randomized to the intervention arm and 459 patients to the standard care arm. Participants in both arms reported high communication quality, high knowledge, and low decisional conflict, demonstrated low accuracy in their risk perception, and would similarly recommend the approach used in their encounter. Clinicians were significantly more satisfied after intervention encounters (400 of 453 encounters [88.3%] vs 277 of 448 encounters [61.8%]; adjusted relative risk, 1.49; 95% CI, 1.42-1.53). A total of 747 of 873 patients (85.6%) chose to start or continue receiving an anticoagulant medication. Patient involvement in decision-making (as assessed through video recordings of the encounters using the Observing Patient Involvement in Decision Making 12-item scale) scores were significantly higher in the intervention arm (mean [SD] score, 33.0 [10.8] points vs 29.1 [13.1] points, respectively; adjusted mean difference, 4.2 points; 95% CI, 2.8-5.6 points). No significant between-arm difference was found in encounter duration (mean [SD] duration, 32 [16] minutes in the intervention arm vs 31 [17] minutes in the standard care arm; adjusted mean between-arm difference, 1.1; 95% CI, -0.3 to 2.5 minutes). The use of an SDM encounter tool improved several measures of SDM quality and clinician satisfaction, with no significant effect on treatment decisions or encounter duration. These results help to calibrate expectations about the value of implementing SDM tools in the care of patients with AF. ClinicalTrials.gov Identifier: NCT02905032.


Long-term outcomes of anthroposophic treatment for chronic disease: a four-year follow-up analysis of 1510 patients from a prospective observational study in routine outpatient settings.
Anthroposophic treatment includes special artistic and physical therapies and special medications. We here report an update to a previously published study of anthroposophic treatment for chronic diseases, including more patients and a longer follow up. The Anthroposophic Medicine Outcomes Study (AMOS) was a prospective observational cohort study of anthroposophic treatment for chronic indications in routine outpatient settings in Germany. Anthroposophic treatment was associated with improvements of symptoms and quality of life. Previous follow-up-analyses have been performed after 24 months or, in subgroups of patients enrolled in the period 1999-2001, after 48 months. We conducted a 48-month follow-up analysis of all patients enrolled in AMOS in the period 1999-2005. 1,510 outpatients aged 1-75 years, starting anthroposophic treatment for chronic conditions in routine German outpatient settings, participated in a prospective cohort study. Main outcomes were Symptom Score (primary outcome, mean symptom severity on numerical rating scales), SF-36 Physical and Mental Component scores in adults, and disease-specific outcomes in the six most common diagnosis groups: asthma, anxiety disorders and migraine (numerical rating scales), depression (Center for Epidemiological Studies Depression Scale), attention deficit hyperactivity symptoms (FBB-HKS Total score), and low back pain (Hanover Functional Ability Questionnaire, Low Back Pain Rating Scale). Median disease duration at baseline was 3.5 years. From baseline to 48-month follow-up all ten outcomes improved significantly (p < 0.001 for all pre-post comparisons). Standardised Response Mean effect sizes were large (range 0.84-1.24 standard deviations) for seven comparisons, medium for two comparisons (SF-36 Mental Component: 0.60, Low Back Pain Rating Scale: 0.55), and small for one comparison (SF-36 Physical Component: 0.39). Symptom Score improved significantly with large effect sizes in adults and children, and in the four main anthroposophic therapy modality groups (art therapy, eurythmy therapy, rhythmical massage therapy, medical therapy). This 48-month follow-up analysis confirmed previous analyses from the AMOS study. Outpatients receiving anthroposophic treatment for chronic indications had sustained, clinically relevant improvements of symptoms and quality of life.


Exploratory machine-learned theoretical chemical shifts can closely predict metabolic mixture signals.
Various chemical shift predictive methodologies have been studied and developed, but there remains the problem of prediction accuracy. Assigning the NMR signals of metabolic mixtures requires high predictive performance owing to the complexity of the signals. Here we propose a new predictive tool that combines quantum chemistry and machine learning. A scaling factor as the objective variable to correct the errors of 2355 theoretical chemical shifts was optimized by exploring 91 machine learning algorithms and using the partial structure of 150 compounds as explanatory variables. The optimal predictive model gave RMSDs between experimental and predicted chemical shifts of 0.2177 ppm for δ 1H and 3.3261 ppm for δ 13C in the test data; thus, better accuracy was achieved compared with existing empirical and quantum chemical methods. The utility of the predictive model was demonstrated by applying it to assignments of experimental NMR signals of a complex metabolic mixture.


Magnetic Resonance Imaging of Cochlear Implant Recipients.
Determine the diagnostic usefulness of postimplantation 1.5 T magnetic resonance imaging (MRI) and review magnet-related MRI complications. Retrospective chart review with additional review of MRIs. Tertiary care children's hospital. Twelve patients who underwent MRI after receiving a cochlear implant (CI). One or more episodes of 1.5 T MRI with CI in place. Occurrence of magnet-related complications; whether imaging was clinically useful. The 12 patients underwent 23 episodes of MRI, including 13 episodes in 11 patients (18 ears) during which a magnet was present and 17 studies were obtained. Complications related to the magnet occurred during 4 of the 13 imaging episodes (30.8%), all during body or spine studies. Magnet torsion with reversal of polarity occurred in three devices; reduced magnet strength in one; and displacement of the magnet from its housing in one. One patient required surgical magnet replacement, whereas other headpiece retention problems were resolved without surgery. All studies but one brain with bilateral magnets were clinically useful. CI patients who undergo MRI with a magnet in situ may experience complications, especially when imaged below the head. Most complications may be resolved without surgery. Diagnostic usefulness of non-cranial MRI is not likely to be limited by presence of the magnet, while a magnet may prevent clinically useful brain imaging. Obtaining MRI with the magnet in situ avoids the cost and risks associated with multiple surgeries to remove and replace the magnet or the entire implant.


Impacts of international sanctions on Iranian pharmaceutical market.
Iran in recent decade faced several regional and international sanctions in foreign trade, financial and banking services. Iran national pharmaceutical industry has always played a major role in providing medicines to the Iranian patients. However, following the sanctions it has faced profound difficulties for importing of both finished products and pharmaceutical raw materials. Although medicines are exempted from sanctions, due to restriction on money transaction and proper insurance Iranian pharmaceutical companies have to pay cash in advance for imports of medicines and raw materials or to secure offshore funds at very high risks. Current situation in Iran pharmaceutical market confirms that the sanctions against Iran are affecting ordinary citizens and national health sector which resulted to reduction of availability of lifesaving medicines in the local market and has caused increasing pain and suffering for Iranian patients.


Predictors of Post-Infectious Chronic Fatigue Syndrome in Adolescents.
This study focused on identifying risk factors for adolescent post-infectious chronic fatigue syndrome (CFS), utilizing a prospective, nested case-control longitudinal design in which over 300 teenagers with Infectious Mononucleosis (IM) were identified through primary care sites and followed. Baseline variables that were gathered several months following IM, included autonomic symptoms, days in bed since IM, perceived stress, stressful life events, family stress, difficulty functioning and attending school, family stress and psychiatric disorders. A number of variables were predictors of post-infectious CFS at 6 months; however, when autonomic symptoms were used as a control variable, only days spent in bed since mono was a significant predictor. Step-wise logistic regression findings indicated that baseline autonomic symptoms as well as days spent in bed since mono, which reflect the severity of illness, were the only significant predictors of those who met CFS criteria at 6 months.


Probing the different chaperone activities of the bacterial HSP70-HSP40 system using a thermolabile luciferase substrate.
During mild heat-stress, a native thermolabile polypeptide may partially unfold and transiently expose water-avoiding hydrophobic segments that readily tend to associate into a stable misfolded species, rich in intra-molecular non-native beta-sheet structures. When the concentration of the heat-unfolded intermediates is elevated, the exposed hydrophobic segments tend to associate with other molecules into large stable insoluble complexes, also called "aggregates." In mammalian cells, stress- and mutation-induced protein misfolding and aggregation may cause degenerative diseases and aging. Young cells, however, effectively counteract toxic protein misfolding with a potent network of molecular chaperones that bind hydrophobic surfaces and actively unfold otherwise stable misfolded and aggregated polypeptides. Here, we followed the behavior of a purified, initially mostly native thermolabile luciferase mutant, in the presence or absence of the Escherichia coli DnaK-DnaJ-GrpE chaperones and/or of ATP, at 22 °C or under mild heat-stress. We concomitantly measured luciferase enzymatic activity, Thioflavin-T fluorescence, and light-scattering to assess the effects of temperature and chaperones on the formation, respectively, of native, unfolded, misfolded, and/or of aggregated species. During mild heat-denaturation, DnaK-DnaJ-GrpE+ATP best maintained, although transiently, high luciferase activity and best prevented heat-induced misfolding and aggregation. In contrast, the ATP-less DnaK and DnaJ did not maintain optimal luciferase activity and were less effective at preventing luciferase misfolding and aggregation. We present a model accounting for the experimental data, where native, unfolded, misfolded, and aggregated species spontaneously inter-convert, and in which DnaK-DnaJ-GrpE+ATP specifically convert stable misfolded species into unstable unfolded intermediates.


ST segment elevation in secondary cardiac cancer: a case report and review of the literature.
Secondary cardiac cancer most frequently originates from primary lung cancer and most commonly occurs in the pericardium. On electrocardiographic examination, patients with secondary cardiac cancer occasionally show ST segment elevation that mimics acute coronary syndrome, despite the absence of coronary artery occlusion. We herein describe a rare case of secondary cardiac cancer that presented with ST segment elevation and review the literature regarding ST segment elevation caused by secondary cardiac cancer. A 73-year-old Japanese woman was admitted to the hospital with chest pain. Electrocardiography showed abnormal ST segment elevation in the precordial and lateral leads, suggestive of ST-elevation myocardial infarction. Emergency coronary angiography showed occlusion of the distal left anterior descending coronary artery (LAD), and plain old balloon angioplasty of the LAD was performed. The ST segment elevation initially resolved after angioplasty, but recurred after 7 days. Contrast-enhanced chest computed tomography showed primary lung cancer in the left lower lobe, pericardial metastasis, and myocardial metastasis in the intraventricular septum and posterolateral wall of the left ventricle. Histopathological examination of the lung cancer was not performed. Patients with ST segment elevation due to secondary cardiac cancer may have symptoms and electrocardiographic changes mimicking anteroseptal or lateral infarction without the development of abnormal Q waves. These findings are frequently associated with posterolateral or anteroseptal invasion by primary lung cancer and may indicate a poor prognosis. In conclusion, physicians should be aware that secondary cardiac cancer may present with symptoms and ST segment elevation mimicking acute coronary syndrome, indicating a poor prognosis.


Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer.
The hantavirus membrane fusion process is mediated by the Gc envelope glycoprotein from within endosomes. However, little is known about the specific mechanism that triggers Gc fusion activation, and its pre- and post-fusion conformations. We established cell-free in vitro systems to characterize hantavirus fusion activation. Low pH was sufficient to trigger the interaction of virus-like particles with liposomes. This interaction was dependent on a pre-fusion glycoprotein arrangement. Further, low pH induced Gc multimerization changes leading to non-reversible Gc homotrimers. These trimers were resistant to detergent, heat and protease digestion, suggesting characteristics of a stable post-fusion structure. No acid-dependent oligomerization rearrangement was detected for the trypsin-sensitive Gn envelope glycoprotein. Finally, acidification induced fusion of glycoprotein-expressing effector cells with non-susceptible CHO cells. Together, the data provide novel information on the Gc fusion trigger and its non-reversible activation involving lipid interaction, multimerization changes and membrane fusion which ultimately allow hantavirus entry into cells.


Continuous postoperative lCBF monitoring in aneurysmal SAH patients using a combined ICP-laser Doppler fiberoptic probe.
Cerebral vasospasm remains the principal cause of morbidity and mortality following successful clipping of intracranial aneurysms. Current management often requires subjective judgments concerning presumed abnormalities of cerebral blood flow. In this study, a combined intracranial pressure (ICP)-laser Doppler flowmetry (LDF) fiberoptic probe that permits continuous monitoring of local cerebral blood flow (lCBF) was used in the postoperative management of 20 aneurysm patients. Using this probe, lCBF was simultaneously recorded and integrated on a real time basis with other physiological parameters, including ICP, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, and pulse oximetry. The combined probe also provided the ability to obtain precise and detailed information concerning the presence or absence of cerebral autoregulation and CO2 vascular reactivity, and allowed calculation of the cerebral vascular resistance. Continuous monitoring of lCBF in this manner complemented by transcranial Doppler and angiographic data permitted early detection of cerebral ischemia, helped to differentiate cerebral ischemia from edema and hyperemia, was useful in titrating blood pressure and fluid management, provided direct feedback about the effectiveness of instituted therapies, and determined early on when medical management was of no avail and that interventional neuroradiology was indicated. Evidence is presented that the presence of angiographic vasospasm and increased velocities on TCD do not always correlate with ischemia in the microcirculation and that direct measurements of lCBF are often at variance with calculations of cerebral perfusion pressure (CPP).


Effects of [3H]glucosamine concentration on [3H]chondroitin sulphate formation by cultured chondrocytes.
GlcN (glucosamine) is now promoted over the counter for implied treatment of osteoarthritis, ostensibly by stimulating biosynthesis of cartilage chondroitin sulphate. In order to evaluate whether exogenous GlcN has any stimulatory effect, we have incubated mouse chondrocytes with [(35)S]sulphate and various amounts of GlcN, to determine whether any increment in chondroitin [(35)S]sulphate formation occurs. Similarly we have used varying concentrations of [(3)H]GlcN to determine the dilution of incorporation into [(3)H]chondroitin sulphate due to provision of endogenous GlcN by metabolism from glucose at two different glucose concentrations. The incorporation of both (35)S and (3)H was essentially linear over a 5 h time period. We found no stimulation of chondroitin [(35)S]sulphate synthesis at lower concentrations of GlcN, and a significant reduction at higher concentrations. Even at concentrations of [(3)H]GlcN that were greater than could be achieved with standard doses of oral GlcN, there was significant dilution of exogenous GlcN. Furthermore, an artificial acceptor for glycosaminoglycan synthesis in cell culture, 4-methylumbelliferyl beta-D-xyloside, did not modify the provision of GlcN from endogenous sources, even though it stimulated chondroitin sulphate synthesis 4 -5-fold at each GlcN concentration. We conclude that the cells have excess capacity to form maximal amounts of GlcN from glucose so that exogenous GlcN does not stimulate chondroitin sulphate synthesis.


History of bleeding and outcomes with apixaban versus warfarin in patients with atrial fibrillation in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial.
History of bleeding strongly influences decisions for anticoagulation in atrial fibrillation (AF). We analyzed outcomes in relation to history of bleeding and randomization in ARISTOTLE trial patients. The on-treatment safety population included 18,140 patients receiving at least 1 dose of study drug (apixaban) or warfarin. Centrally adjudicated outcomes in relation to bleeding history were analyzed using a Cox proportional hazards model adjusted for randomized treatment and established risk factors. Efficacy end points were analyzed on the randomized (intention to treat) population. A bleeding history was reported at baseline in 3,033 patients (16.7%), who more often were male, with a history of prior stroke/transient ischemic attack/systemic embolism and diabetes; higher CHADS2 scores, age, and body weight; and lower creatinine clearance and mean systolic blood pressure. Major (but not intracranial) bleeding occurred more frequently in patients with versus without a history of bleeding (adjusted hazard ratio 1.35, 95% CI 1.14-1.61). There were no significant interactions between bleeding history and treatment for stroke/systemic embolism, hemorrhagic stroke, death, or major bleeding, with fewer outcomes with apixaban versus warfarin for all of these outcomes independent of the presence/absence of a bleeding history. In patients with AF in a randomized clinical trial of oral anticoagulants, a history of bleeding is associated with several risk factors for stroke and portends a higher risk of major-but not intracranial-bleeding, during anticoagulation. However, the beneficial effects of apixaban over warfarin for stroke, hemorrhagic stroke, death, or major bleeding remains consistent regardless of history of bleeding.